Interpreting iron studies

BMJ 2017;357:j2513 doi: 10.1136/bmj.j2513 (Published 2017 June 15)

Practice

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PRACTICE

RATIONAL TESTING

Interpreting iron studies

Alison U Kelly specialty registrar in chemical pathology 1, Stephen T McSorley clinical research fellow 2, Prinesh Patel general practitioner 3, Dinesh Talwar consultant clinical scientist 1

1Department of Biochemistry, Glasgow Royal Infirmary, Glasgow, UK; 2Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK; 3Alva Medical Practice, Alva, Stirlingshire, UK

A 63 year old woman visits her doctor with a three month history of fatigue and generalised joint pains. Her medical history is unremarkable and she reports no recent stress, infection, or weight loss. There are no abnormalities on clinical examination. Haemoglobin, creatinine, and electrolytes, liver enzymes, glucose, inflammatory markers, and thyroid function tests are normal. Ferritin, iron, transferrin, and transferrin saturation are also requested.

This article discusses some situations in which ferritin and iron studies might be helpful and how to avoid common pitfalls in their interpretation.

What are the next investigations?

The doctor in this case requested iron studies to investigate the possibility of iron overload and to screen for haemochromatosis. Iron studies are also commonly indicated in clinical practice to investigate iron deficiency, or to monitor response to treatment for these conditions (box 1).

Conventional laboratory tests of iron status are often referred to as "iron studies." They include tests for serum ferritin, iron, transferrin, or total iron binding capacity (TIBC), and transferrin saturation.

Iron is a key component of haemoglobin in red blood cells, myoglobin in muscle, and many metalloproteins and enzymes. It is essential for uptake of oxygen and its delivery to tissues, utilisation of oxygen by muscle cells, and mitochondrial energy production.3 Normal iron metabolism and regulation is outlined in Figure 1. The adult male body contains 3-5 g of iron. Less than 0.1% of total body iron stores circulate in plasma. Dietary Fe3+ is reduced to Fe2+ and transported into the enterocyte by the divalent metal transporter DMT1. Iron is exported across the basolateral membrane via the iron export protein ferroportin 1 or stored as ferritin. Transferrin bound iron binds to transferrin receptor 1 (TFR1) and is taken up into the cell via receptor mediated endocytosis. Expression of TFR1 is regulated locally by the iron demands of the cell, via binding of iron regulatory proteins. Old or damaged erythrocytes are removed from the

circulation by splenic macrophages. Iron is removed from haem by haem oxygenase 1, and either stored as ferritin or released into the circulation.

Regulation of iron release at a systemic level is mediated by the peptide hormone hepcidin (produced predominantly by hepatocytes) and has an inhibitory effect on iron release from cells and dietary iron absorption. Expression is controlled by complex signalling pathways.1

What is included in iron studies?

Ferritin--is the intracellular storage form of iron. A very small amount is found in serum. In inflammation, liver disease, and malignancy, ferritin levels can rise because ferritin is an acute phase protein.4 In these patients, ferritin can appear either falsely high or normal, when in reality stores are low.

Serum iron--refers to ferric ions (Fe3+) bound to serum transferrin. Serum iron concentration is highly variable and is affected by dietary iron intake, inflammation, and infection.5

Transferrin--is the principal iron transport protein in plasma. It increases in iron deficiency to maximise utilisation of available iron.4 Total iron binding capacity is an alternative test to transferrin. TIBC reflects the availability of iron binding sites on transferrin. Values increase in iron deficiency and decrease in iron overload. Some laboratories measure unsaturated iron binding capacity (UIBC) and calculate TIBC by adding serum iron to UIBC.

Transferrin saturation--is calculated from serum iron and either TIBC or transferrin measurements. Typically, transferrin is 30% saturated with iron.5 Transferrin saturation rises in iron overload and falls in iron deficiency, but does not quantitatively reflect iron stores.1 A rise in serum iron due to dietary iron intake can cause raised transferrin saturation.

Correspondence to A U Kelly alison.kelly7@

For personal use only: See rights and reprints

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BMJ 2017;357:j2513 doi: 10.1136/bmj.j2513 (Published 2017 June 15)

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What you need to know ?Iron overload typically results in a high ferritin and transferrin saturation ?Iron deficiency is best assessed using serum ferritin, which is low in the absence of inflammation ?Ferritin levels can be elevated by inflammatory processes and can mask iron deficiency

Box 1: Suggested indications for iron studies

Investigation of ? iron overload (haemochromatosis)1 o at early stages can be asymptomatic or present with vague symptoms such as fatigue, weakness, or generalised joint pains o later manifestations might include deranged liver enzymes, cirrhosis, erectile dysfunction, arthritis, or cardiomyopathy o suspected iron overdose/toxicity

? iron deficiency2 o investigating aetiology of low haemoglobin o symptoms of anaemia--such as lethargy, shortness of breath, palpitations, pallor, headache, atrophic glossitis, angular cheilosis. Suspected occult blood loss in males and post menopausal females--eg, peptic ulcer disease o menorrhagia o iron malabsorption--eg, investigation of unintentional weight loss or chronic diarrhoea, or secondary to existing conditions such as coeliac disease o Anaemia in pregnancy (increased iron demands) o investigation of poor growth in infants o distinguishing low iron stores from functional iron deficiency--eg, in chronic kidney disease

? response to medical treatment o monitoring patients who require repeated transfusions or venesection o monitoring response to iron chelators o assessing response to iron therapy

Interpretation

Interpretation of iron studies can be challenging because the difficulties listed above affect almost all markers of iron status. Nevertheless, iron studies play an important role in clinical assessment (table 1). Reference intervals are quoted; however, these can vary by laboratory and must be confirmed locally.

Iron overload

Testing for iron overload (increased total body iron stores with or without organ dysfunction) can be triggered by clinical features such as those listed in box 1. Primary iron overload includes inherited mutations in iron regulatory genes (causing iron loading syndromes such as haemochromatosis). Secondary iron overload is associated with other conditions or iatrogenic factors (box 2).

Hereditary haemochromatosis (an autosomal recessive genetic condition caused by mutation of the HFE gene) is the most common inherited cause of iron overload. Homozygosity for the C282Y polymorphism affects 1 in 200 people of northern European descent and accounts for more than 80% of clinically recognised cases. Clinical penetrance varies widely (1%-28% of C282Y homozygotes in population studies).7 In an unselected population, raised serum ferritin (>200 g/L for premenopausal women or >300 g/L for men and postmenopausal women) and transferrin saturation >50% diagnosed C282Y homozygosity with a sensitivity of 90% in men and 75% in women.8 An approach to hyperferritinaemia has previously been discussed.6

Specialist techniques for assessing iron overload include liver biopsy, magnetic resonance imaging, and superconducting quantum interference device susceptometry, a non-invasive technique that measures the amount of in vivo magnetisation caused by hepatic iron.1 Indications for these tests can include marked hyperferritinaemia (>1000 g/L) or further assessment when the diagnosis of iron overload is in doubt. They are not widely available and are usually requested by specialists.

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Tips on requests and interpretation

? Request serum ferritin and transferrin saturation together to assess for iron overload, alongside haemoglobin to identify anaemia and aid treatment decisions (eg, venesection).

? If elevated transferrin saturation is the only biochemical abnormality or the result is borderline, repeat the test on a fasting sample to eliminate a rise caused by dietary iron.

? If transferrin saturation is persistently raised, offer HFE gene analysis with pre-test counselling.

? In C282Y homozygotes, transferrin saturation is the first biochemical parameter to rise. Serum ferritin might be normal in the early stages of the disease, however some patients later develop clinically significant iron overload7 (organ dysfunction with or without symptoms). Annual monitoring of serum ferritin is proposed in established guidelines.1 In the absence of local defined protocols, consider referral for further assessment if hyperferritinaemia develops or ferritin is progressively rising.

? Ingestion of therapeutic iron (including iron containing multivitamins) can raise transferrin saturation to levels reaching 100%,5 and based on our clinical experience we recommend waiting four weeks after cessation of treatment before requesting serum iron, transferrin/TIBC, and transferrin saturation.

? High iron, transferrin, transferrin saturation, and serum ferritin can be seen in acute hepatic injury due to leakage of intracellular contents, and can incorrectly give the impression of iron overload.5

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BMJ 2017;357:j2513 doi: 10.1136/bmj.j2513 (Published 2017 June 15)

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Box 2: Causes of iron overload6 Primary

Inherited mutations in iron regulatory genes (eg, haemochromatosis)

Secondary to other conditions/iatrogenic factors Repeated blood transfusion (eg, beta thalassaemia, sickle cell anaemia) Iron loading anaemias (eg, beta thalassaemia, sideroblastic anaemias, chronic haemolytic anaemia, aplastic anaemia) Iron and iron containing supplements (enteral and parenteral) Porphyria cutanea tarda (hepatic iron accumulation)

Investigating iron deficiency

Biochemical definitions are listed in box 3.9. Low serum ferritin (6%) is recommended for diagnosis of iron deficiency in chronic kidney disease if the sample can be processed within six hours; however, this might be precluded by availability of laboratory services. Reticulocyte haemoglobin content ( ................
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